1. Field of the Invention
The present invention relates to a human Rgr protein and naturally-occurring variants thereof, in particular, abnormally truncated variants found in T cell malignancies. The present invention also relates to antibodies that bind to the human Rgr protein and/or to naturally-occurring variants thereof and to nucleic acid molecules encoding human Rgr protein and naturally-occurring variants thereof.
2. Description of the Related Art
Analysis of the molecular bases of cancer have resulted in the identification of a number of genetic alterations affecting a subset of genes involved in control of proliferation, survival and differentiation. Oncogenes are one of the most prominent groups of genes involved in the pathogenesis of cancer and they often exert their transforming effects by subverting the normal signal transduction pathways in the host cell.
The laboratory of the present inventors first identified the rgr oncogene as one of the two components present in the rsc oncogene (D'Adamo et al., 1997), which was isolated from a DMBA-induced rabbit squamous cell carcinoma using gene transfer and the nude mouse tumorigenesis assay (Leon et al., 1988). Rgr is highly homologous to RalGDS, with a 40% overall identity, increasing to 72% over a 100 amino acid region. RalGDS is a guanine nucleotide exchange factor (GEF) that activates its effector, the Ral GTPase, by dissociating the bound GDP and allowing the binding of GTP which results in RalGDS activation (Albright et al., 1993; White et al., 1996). Like RalGDS, Rgr also dissociates GTP from Ral A (D'Adamo et al., 1997). The laboratory of the present inventors have further shown that rgr induces phosphorylation of ERKs, p 38, and JNK kinases, and it increases the levels of GTP bound Ral and Ras (Hernandez-Muñoz et al., 2000). The importance of these activities is confirmed by experiments in which dominant negative Ras, Ral, and Rho block the transcription activation induced by rgr. However, only dominant negative Ras inhibits rgr transformation, indicating that Ras activation is crucial for the transforming activity of rgr (Hernandez-Muñoz et al., 2000).
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